Drug-virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model

Abstract

Modern cancer therapy combines recombinant viruses with traditional chemotherapeutic agents that are metabolized by hepatic cytochrome P450 3A4 (CYP3A4). A single dose of recombinant adenovirus (Ad) expressing beta-galactosidase (AdlacZ) significantly alters CYP3A2, the correlate of CYP3A4, in rats for 14 days. Recombinant adenovirus expressing human p53 (Adp53) also suppresses CYP3A2. Plasma clearance of docetaxel (DTX) in animals given AdlacZ (3.38+/-0.22 l h(-1) kg(-1)) was significantly lower than that of those given DTX alone (7.35+/-1.22 l h(-1) kg(-1), P<or=0.05). Area under the plasma concentration-time curve of DTX in rats given AdlacZ (2987.37+/-197.97 ng ml(-1) h(-1)) was significantly greater than those given drug alone (1496.14+/-281.62 ng ml(-1) h(-1), P<or=0.05). Both viruses prolonged DTX half-life (t(1/2)). Ad infection may cause significant variability in the pharmacokinetics and pharmacodynamics of anti-cancer agents and should be considered when designing therapeutic regimens for patients with viral infection and those enrolled in clinical trials using recombinant viruses.

Figure 1. Systemic administration of recombinant adenoviral vectors suppresses hepatic CYP3A2 24 hours after treatment

(a) In vitro catalytic activity of CYP3A2 microsomal proteins measured by the production of testosterone metabolite, 6β-hydroxytestosterone. (b) Western blot analysis of hepatic CYP3A1/2 protein expression. (c) mRNA levels of CYP3A2, as determined by real time RT-PCR. (d) Effect of systemic administration of adenovirus on serum aspartate aminotransferase (AST). (e) Effect of systemic administration of adenovirus on serum alanine aminotransferase (ALT). Results are reported as the mean ± the standard error (SE) of the mean; n = 4-5 rats per treatment group. *P ≤ 0.05, **P ≤ 0.01, *** P ≤ 0.001 with respect to vehicle control (PBS).

Figure 2. Recombinant Adenoviruses Alter the Pharmacokinetic parameters of DTX

(a) Observed plasma concentration-time curve after intravenous administration of DTX (10 mg/kg) to animals given the drug alone (DTX) and those treated with recombinant adenoviruses 24 hours earlier (AdlacZ + DTX, Adp53 + DTX). (b) Tissue distribution of DTX 24 hours after administration in the presence and absence of recombinant adenoviruses. Results are reported as the mean ± SE; n = 4-5 rats per treatment group. *** P ≤ 0.001 with respect to vehicle control (PBS).

Figure 3. DTX Does not Alter the Pattern of Virus-Induced Changes in Hepatic CYP3A2 Expression and Function

(a) In vitro catalytic activity of CYP3A2 microsomal proteins measured 48 hours after administration of either adenovirus alone or in combination with DTX. (b) Western blot analysis of liver microsomal proteins for CYP3A1/2. (c) Gene expression of CYP3A2, as determined by real time RT-PCR. Results are reported as the mean ± SE; n = 4-5 rats per treatment group. *P ≤ 0.05, **P ≤ 0.01, *** P ≤ 0.001 with respect to vehicle control (PBS).

Figure 4. Systemic administration of DTX can increase serum transaminases 24 hours after treatment

Serum (a) AST and (b) ALT levels. Results are reported as the mean ± SE; n = 4-5 rats per treatment group. **P ≤ 0.01, *** P ≤ 0.001 with respect to vehicle control (PBS).

Figure 5. DTX does not effect hepatic transgene expression and virus distribution

(a) Representative hepatic tissue section 24 hours after intravenous administration of AdlacZ. (b) Representative tissue section 48 hours after intravenous administration of the same virus. (c) Representative tissue section from an animal treated with AdlacZ and then DTX 24 hours later (sacrificed 48 hours after administration of virus). (d) Beta-galactosidase expression, as measured by ELISA, in the liver 48 hours after administration of either AdlacZ alone or in combination with DTX. (e) p53 expression, as determined by RT-PCR. (f) Distribution of viral genomes in the liver following systemic administration of either adenovirus alone or in combination with DTX. (g) Distribution of virus in the lung after administration of either virus alone or in combination with DTX. (h) Distribution of viral genomes in the kidney following systemic administration of either adenovirus alone or in combination with DTX. Results are reported as the mean ± SE; n = 4-5 rats per treatment group.